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10. neural stem cells of the brain and their theraputic potential Flashcards

1
Q

give one factors that help reduce the risk of Alzheimer’s

A

good cardiovascular health

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2
Q

where are NSC normally found? and what function may this have?

A

clustered new to blood vessels

this may maintain NSC quiescence

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3
Q

what are neural stem cells and what do they produce?

A

they are tissue specific stem cells that generate neurons, oligodendrocytes and astrocytes

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4
Q

in comparison to neurons, how many astrocytes are there in the brain?

A

there are ten times as many astrocytes as there are neurones in the brain

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5
Q

what do oligodendrocytes do?

A

they en-sheath axons to allow for fast nervous transmission

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6
Q

what cell type are attacked in MS?

A

oligodendrocytes

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7
Q

can oligodendrocytes be made in the adult brain?

A

yes

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8
Q

in early stages of development, part of the rapidly dividing ball of cells is given signals to become brain and not … ?

A

skin

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9
Q

development is coordinated by surrounding tissue. what type of signal defines the front from the back of the embryo?

A

morphogen gradients

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10
Q

once the potency of developing embryos CNS is down to neural stem cells, what happens?

A

neurones are generated in the correct place at the right time. these migrate to their final position. glial cells are produced. synapses are generated and excess neurones are culled.

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11
Q

what occurs in the brain throughout life?

A

remodelling and fine tuning, new synapses are formed and synapses the brain decides not to keep are lost

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12
Q

in early development, what are dopaminergic neurons made from?

A

radial glia

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13
Q

in early development, where are radial glia?

A

radial glia span the neural tube

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14
Q

what is the ventral filled with and what is this like in early development?

A

it is filled with cerebral fluid, it is very larger in early development

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15
Q

once radial glia have made enough dopaminergic neurones they switch to making what type of cell?

A

they make glia which support the dopaminergic neurones

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16
Q

describe how dopaminergic neurones are produced in early development?

A

radial glia exit the cell cycle at the ventricular zone and become DN, they wriggle down radial glia to their final position at the edge of the ventricle of the normal tube and grow axons into the forebrain

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17
Q

why is it important to know what transcription factors regulate development?

A

so that we can copy it in a dish and direct ESC/iPSC into neurons

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18
Q

what two methods can be used to see what transcription factors are being expressed?

A

FISH and transcriptome analysis (RNA-seq)

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19
Q

why is there post-natal development in the brain?

A

for memory formation

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20
Q

why is it very hard to generate new neurones in most of the post-natal brain?

A

during the course of evolution cell division in the brain has been stopped in most regions to reduce the risk of cancer

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21
Q

in what two regions of the brain has the brain decided it is worth the risk of post-natal neuronal development to occur?

A

striatal subventricular zone (SVZ) and subgranular zone (SGZ)

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22
Q

where is the subgranular zone located?

A

in the hippocampus

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23
Q

what are the neural stem cells of the subventricular zone?

A

they are a type of glia

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24
Q

neural stem cells of the subventricular zone have cilia, what it their function?

A

they have wafting cilia that wash away the waste in our brain as we sleep, this may be why lack of sleep kills

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25
when are the subventrciular zone neural stem cells located?
either directly in contact with or just below the ventricle
26
what do subventricular zone stem cells become? following this, what can be observed in rodents?
neuroblasts migrate in chains through the rostral migratory stream to the olfactory bulb where they form functioning circuits
27
what else can NSC of the SVZ make?
oligodendrocytes
28
why do rodents have a large olfactory bulb and what is the human olfactory bulb like?
rodent rely on smell much more than we do | the human olfactory bulb is shrivelled and basic
29
when neuroblasts reach the olfactory bulb of rats, what do they become?
GABAergic and dopaminergic interneurons
30
has an rostral migratory system ever been identified in humans?
no
31
what do the neuroblasts of the SVZ in humans become? and where do they go?
striatal interneurons | they go to different regions of the brain that is not the olfactory bulb
32
why is the progeny of these SVZ neuroblasts clinically relevant?
- striatal interneurons are depleted in Huntington's | - something in about these cells are venerable in this disease
33
what does a transcription factor programme do in development?
narrow down the potency of a cell
34
what sort of information is important for the adult neural stem cells of the SVZ?
positional information | this information is integrated from all axis
35
what can be used to follow the daughter cells of SVZ NSC? and what did the use of these identify in rats?
genetic labels | these identified four new subtypes of interneurons produced in a specific micro-domain of the SVZ
36
smell and memory is very important to rodents. how many new neurons do they produce a day?
20,000-30,000
37
how do the NSC progeny differ in from embryonic and neonatal NSC progeny?
they have delayed firing and they are more excitable
38
what is the hippocampus important form?
new memory formation
39
what are the two potential fates of memories formed in the hippocampus?
the brain will decide to remember them or forget them if it does not think you will need them in the future
40
what has the hippocampus been seen to do with memories?
link them
41
what two things can boost new neuron formation in the SGZ?
exercise and new experiences
42
what reduces the number of new neurons produced in the SGZ?
chronic stress - the level of cortisol in blood
43
when a rodent is bored, what is seen in its hippocampus? and what happens when you give him stimuli?
- not many new neurones are born | - they will start making new neurones
44
what type of NSC are in the SGZ?
they are astrocyte-radial glia like hybrid cells
45
sox2 is highly expressed in NSC, why?
it is key for telling a cell that it is going to be neural
46
neural stem cells in the brain are hard to find, as soon as you dissociate the brain what happens?
almost all the cells die
47
what can do NSC of the GVZ generate?
glutamatergic dendrite granule cells in the hippocampus
48
briefly describe the developmental program of neural cells
NSC are programmed to be neural, they start to make specific subtypes of neurones due to the signals that they receive, they migrate and integrate into the neural circuitry
49
how many new neurones are generated in the human hippocampus each day?
700
50
how was it possible to see that human brain produced new neurones?
in the 1950s there were nuclear bomb tests, cells that divided in this time incorporated radioactive carbon into their genome, when these brains were donated they could show that the brain contains new neurones
51
what is the function of adult neurones generated from SGZ? (4)
spatial learning, fear conditioning, clearing memory traces and navigation
52
what two conditions has the hippocampus been linked whit?
depression and autism
53
what is through to be happening in the hippocampus when people suffer from depression?
they are less able to make new memories/neurones or they are less able to disrupt hippocampus mature circuitry - their brain my lock them into a negative memory loop
54
why has the hippocampus been linked to people on the autistic spectrum?
they remember everything
55
what are serotonin reuptake inhibits used for and what do they do?
they are given to people with depression. they boost the serotonin signalling and increase hippocampus neurogenesis
56
what therapy has also been shown to increase hippocampus neurogenesis in animal models?
electroconvulsive therapy
57
what is one of the causes of temporal lobe epilepsy? and what in the future may potentially rescue this?
- improper excitability in the hippocampus due to a lack of neurones in the hippocampus - grafting new NSC (genetically corrected using CRISPR) into the hippocampus
58
name four factors that contribute to the adult NSC niche?
1. blood 2. surrounding neurones 3. glia cells 4. extracellular matrix/physical force
59
what signal keeps NSC quiescent? and what function may this have?
BMP | supressing cell cycle genes and promoting genes for stemness
60
what factor is found in blood that maintains quiescence and how does it function?
PEDF (pigment epithelial derived factor) upregulates Notch signalling, this prevents differentiation and promotes self-renewal
61
what may bring SGZ NSC out of quiescence?
stem cell monitor electrical activity around them, when dentate granule cells are damaged they no longer leak GABA from their synapses and this signals NSC to come out of G0 to produce new neurones
62
what might over excitation of GABA/glutamate neurones around SGZ NSC do?
it might kill NSC and drive disease, this might be happening in some epilepsies
63
what happens to neurogenesis as people age?
there are fewer, less proliferative NSC, which are less efficient
64
what happens when aged NSC are made into neurospheres?
less ki67 is observed, this is expressed during all active stages of the cell cycle
65
what is heterochronic parasymbiosis?
when the circulation of a young and old mouse is connected
66
what has young mice blood been shown to do?
reverse age related impairments in cognitive function and synapse plasticity - more NSC and neuroblasts seen in old brain - more dendritic spines of new neurones observed
67
how do brain tumour arise?
when unwanted adult neurogenesis occurs
68
what is GBM?
Glioblastoma Multiforme, the most common type of CNS tumour
69
what is the mean survival time of GBM?
14-16 months with surgery, radio- and chemotherapy
70
when multiple GBM were profiled what was observed?
the amplifications of two receptor tyrosine kinases
71
what does ALS stand for and what is it?
Amyotrophic lateral sclerosis is a type of motor neurone disease where motor neurones in the spinal cord and motor cortex die, this can be fatal
72
why is it useful to be able to model ALS from iPSC? (3)
- not much is known about why motor neurones die - there is currently only one treatment which is not very effective and only helps some people for a short period of time - it means that we do not need to probe a person that is in agony
73
what was seen when sequencing genome of an 82year old ALS sufferer?
a rare L144F dominant allele mutation in SOD1 associated with her slow progression form of ALS
74
when iPSC are generated from a patient, what two things need to be checked?
- check that they are pluripotent | - check that they still carry the disease causing mutation
75
what does the lack of SOD1 function result in?
SOD1 is a free radical scavenger enzyme and so her motor neurones were being attacked by free radicals much more than they should be
76
what should iPSC be treated with to make motor neurones? (3)
Shh retinoic acid agonist grown on laminin
77
what two things did a small molecule screen on ALS cells show?
- it identified why two drugs did not work as they had not effect on neurones - they also identified a kinase inhibitor that prolonged healthy survival of ALS motor neurones
78
which kinases were these driving ALS and what were they doing?
GSK-3 and HGK kinases were killing motor neurons
79
what is Rett syndrome?
a progressive X-linked neurological disorder
80
what gene is effected in Rett syndrome, what does it do and how often is it mutated?
MeCP2, a methyl CpG binding proteins, which is essential for the function of nerve cells, mutated in 95% of cases
81
what is the symptoms of Rett disease?
child has normal development until 18 months. then child has motor neurone decline, weak muscle tone, seizures and autistic behaviour.
82
what is seen in neurones made from Rett patient iPSCS? (4)
- they have fewer synapses - reduced spine density - altered calcium signalling - electrophysiological defects
83
what happened when choline was added to rett syndrome neurones generated from iPSCs?
it rescued the number of synapses formed
84
what happens neurones die in Parkinson’s disease?
dopaminergic neurons
85
why is it stressful being a DN?
they are large, with long projections and are constantly firing for decades
86
what is a good marker of DN?
tyrosine hydroxylase is the rate determining enzyme in dopamine synthesis
87
what is seen in DN in Parkinson’s disease?
alpha-synuclein protein aggregates
88
is it known why DN die in Parkinson's?
no, but a kinase defect LRRK2 is seen in some types of Parkinson's
89
what are the symptoms of Williams syndrome?
hyper-social and altered linguistic and cognitive ability
90
what was seen in neurones generated from Williams syndrome patients? (3) and what is through to be contributing to this?
- cells were firing more often - increased number of dendritic spines - cells made more synapses Wnt frizzled receptor 9 and so is a potential therapeutic target
91
what does Alzheimer’s disease Brain tissue contain? and what does this results it?
amyloid plaques which result in the formation of neurofibrillary tangles and neuronal death
92
what do iPSCs open the door to?
personalised medicine - it will be possible to test the effectiveness of a treatment on someone before they are treated
93
what are cerebral organoids used to study?
brain development and microcephaly
94
what ethical issues have been raised about the use of cerebral organoids?
the potential to raise consciousness
95
name the disease that is characterised by a small head and too few neurones, giving some symptoms of this disease
microcephaly causes cognitive problems and is very painful
96
what is zika virus causing?
zika virus is causes microcephaly and additional neuronal cell death
97
what did cerebral organoids show about microcephaly?
they showed that the spindle formation in microcephaly was wrong and this lead to not enough symmetrical division of radial glia before they differentiated and therefore not enough neurones
98
what is a therapeutic use of NSC that has been trialled?
replacing diseased DN in patients with Parkinson’s
99
what are two consideration that needs to be made when considering NSC in therapeutics?
that they do not give rise to cancers, they do not form abnormal connections and they do not trigger an immune response

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